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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
WWP2 is an E3 ubiquitin ligase for PTEN
Subbareddy Maddika1, Sridhar Kavela, Neelam Rani
1Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India. msreddy@cdfd.org.in
Nature Cell Biology
|May 3, 2011
Summary
WWP2, an E3 ubiquitin ligase, interacts with PTEN (phosphatase and tensin homolog) and targets it for degradation. This WWP2-mediated PTEN degradation is crucial for controlling cancer cell survival and tumorigenicity.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- PTEN (phosphatase and tensin homolog) is a critical tumor suppressor frequently mutated in human cancers.
- Ubiquitylation plays a role in regulating PTEN's tumor suppressor function, but the specific enzymes involved are not fully understood.
Purpose of the Study:
- To identify the E3 ubiquitin ligase responsible for PTEN ubiquitylation.
- To investigate the functional consequences of WWP2-mediated PTEN degradation in cancer.
Main Methods:
- Tandem affinity-purification to identify PTEN-interacting proteins.
- Ubiquitylation assays to confirm WWP2's ligase activity towards PTEN.
- Functional assays assessing apoptosis and tumorigenicity.
Main Results:
- WWP2 (also known as atrophin-1-interacting protein 2, AIP-2) was identified as a PTEN-interacting protein.
- WWP2 directly mediates PTEN degradation via a ubiquitylation-dependent pathway.
- WWP2 is essential for cancer cell survival by controlling apoptosis and tumorigenicity.
Conclusions:
- WWP2 is a functional E3 ubiquitin ligase for PTEN.
- The WWP2-PTEN axis is a key regulator of tumor cell survival and presents a potential therapeutic target.
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